The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.

Objective To explore drug use patterns in treatment of lung cancer patients after surgery based on data mining.Methods The prescriptions of patients with lung cancer who were diagnosed and treated in the outpatient department of the First Affiliated Hospital of Anhui University of Chinese Medicine from September 2009 to December 2023 were collected.Based on the Cloud Platform of Ancient And Modern Medical Records,data mining method was used to analyze the nature and taste of drugs,meridian affinity,frequency,association rule,cluster and core prescription complex network.Results A total of 171 traditional Chinese medicine prescriptions were collected,involving 156 traditional Chinese medicines,and the top three drug effects were eliminating annoyance,stopping vomiting,clear heat and remove toxins.The main channel was the lung meridian,nature and taste were mainly slightly cold,flat and sweet.The high frequency(frequency＞30 times)drugs included 20 flavors such as coastal glehnia root,bamboo shavings,and liquorice root.There were 5 cluster analysis combinations and 83 associationrules.The core prescriptions were coastal glehnia root,bamboo shavings,liquorice root,reed rhizome,platycodon root,inner fiber of orange peel,spine date seed,milkwort root,dwarf lilyturf tuber,hairyvein agrimonia herb.Conclusion After surgery,lung cancer should be treated from the lung and spleen,following the prescription principles of light spirit,increasing and decreasing with the syndrome,reinforce healthy qi to eliminate pathogenic factors,and eliminating phlegm.

Objective:To investigate the correlation between Piwi-interacting RNA (piRNA) and diabetic nephropathy (DN).Methods:The differential expression profiles of piRNAs in renal tissues of patients with DN (experimental group) and renal tissues adjacent to tumors of patients with renal tumors (control group) were detected by high-throughput sequencing. The biological function of differentially expressed piRNAs was described by gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis. Real-time fluorescence quantitative PCR was used to detect the serum expression level of target piRNAs in patients with DN. Spearman correlation analysis was used to analyze the correlation between serum target piRNAs and clinical indexes of patients with DN.Results:The results of high throughput sequencing showed that there were 127 differentially expressed piRNAs between DN group and control group, with screening condition of |log 2(fold changes)|≥2 and P<0.05. Among them, there were 99 up-regulated piRNAs and 28 down-regulated piRNAs. The top 5 up-regulated piRNAs were piRNA-hsa-161686, piRNA-hsa-349255, piRNA-hsa-355720, piRNA-hsa-151229 and piRNA-hsa-154959, respectively. The top 5 down-regulated piRNAs were piRNA-hsa-1929960, piRNA-hsa-174194, piRNA-hsa- 148658, piRNA-hsa-172594 and piRNA-hsa-172421, respectively. The PCR verification results of 3 up-regulated genes and 3 down-regulated genes with low P values and high expression levels showed that serum expression level of piRNA-hsa-77976 was significantly down-regulated in patients with DN ( P=0.028), which was consistent with that of sequencing, while the expression levels of other genes were inconsistent with the sequencing results or had no statistical significance. Bioinformatics analysis results predicted that significantly differentially expressed piRNAs might participate in the regulation of DN through Rap1, Ras, PI3K-Akt and axon guiding pathways. The results of correlation analysis showed that the expression level of piRNA-hsa-77976 was negatively correlated with blood urea nitrogen ( r=-0.584, P=0.028), serum creatinine ( r=-0.637, P=0.014), cystatin C ( r=-0.738, P=0.003) and β2 microglobulin ( r=-0.822, P<0.001), and positively correlated with estimated glomerular filtration rate ( r=0.661, P=0.010). Conclusion:The differential expression of piRNA is closely related to DN, and may be used as a new biomarker for the diagnosis and prognosis of DN.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

Objective:We aimed to observe the effects of loganin(Log)on serum glycolipid levels and probe the mechanisms focusing on intestinal flora and AMP-activated protein kinase(AMPK)signaling in obese mice.Methods:A high-fat diet was given for 12 consecutive weeks to generate the obesity model in institute of cancer research(ICR)mice.Body weight was measured weekly and fasting blood glucose(FBG)was determined every 2 weeks.Both the oral glucose tolerance test and the intraperitoneal insulin tolerance test were performed.The serum levels of total cholesterol(TC),triglyceride,high-density lipoprotein-cholesterol,low-density lipoprotein-cholesterol(LDL-C),and free fatty acids(FFA)were measured.The expression of key proteins in the AMPK signaling pathway in skeletal muscle tissue was detected by immunoblotting,and gut microbiota were characterized using 16S rDNA sequencing.Results:Log significantly decreased the body weight and the FBG in obese mice(P＜.05),and it could restore FBG to normal levels.The total cholesterol,LDL-C,and FFA levels were significantly reduced by Log compared with the obese controls(TC:P=.0020;LDL-C:P=.0233;FFA:P=.0127),and the glucose tolerance of animals was significantly improved(P=.0477).The western blot results showed that Log could upregulate the protein expression of Adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPKα),Sirtuin 1(SIRT1),and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha(PGC1α)in skeletal muscle tissue of obese mice.16S rDNA sequencing indicated that Log reduced the diversity of the gut flora in feces and altered the floral composition of obese mice.Conclusions:Log was effective in reducing body weight and improving glucolipid metabolism in obese mice,probably through activating AMPK signaling and regulating intestinal microbial diversity.

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

Objective:To compare the efficacy of traditional open thyroidectomy and modified Miccoli in the treatment of benign thyroid diseases.Methods:The data of 343 patients with benign thyroid disease in Xi′an Central Hospital and Xi′an Third Hospital were retrospectively analyzed. According to the surgical method, the patients were divided into the observation group (modified Miccoli operation, n=169) and the control group (traditional open operation, n=174). The operation effect, postoperative recovery, patient satisfaction, postoperative complications and recurrence within 1 year of follow-up were compared between the two groups.Count data were represented by n(%), measurement data consistent with normal distribution were represented by Mean± SD, and non-normal data were represented by M( P25, P75). T test or Wilcoxon rank sum test were used to compare the measurement data between groups according to their distribution characteristics. Comparison of statistical data between groups was made by chi-square test. Results:The intraoperative blood loss and postoperative drainage volume of the patients in the observation group were 26.2 (6.9, 40.8) ml and (33.4±8.6) ml, respectively, which were significantly less than those in the control group 50.6 (37.5, 63.7) ml and (35.7±9.5) ml (all P<0.05). The postoperative recovery time in the observation group was (3.9±2.8) d, which was significantly shorter than that in the control group (5.1±2.4) d ( P=0.001). Postoperative complications such as hoarseness, subcutaneous ecchymosis, scar formation and decreased parathyroid function were significantly different between the two groups ( P<0.05). The recurrence rate of 7.69% in the observation group was significantly lower than that of 19.54% in the control group 12 months after operation ( P<0.05). Conclusions:The modified Miccoli in the treatment of benign thyroid diseases not only has the advantages of less trauma, faster postoperative recovery, less pain and higher patient satisfaction, but also has lower postoperative complications and recurrence rate, which is worthy of clinical promotion and application.

Insomnia is a common disorder in the elderly and seriously affects life quality of the elderly.This article reviews the efficacy and safety of pharmacological agents for the treatment of insomnia in the elderly, in order to provide a reference for clinical practice.

Aim To investigate the effect of curcumin against high-fat-diet induced C57BL/6J mice bone changes and the correlation between the expression of cathepsin K and curcumin.Methods Curcumin treated C57BL/6J mice had been on high fat diet for 12 weeks.The HE, Alizarin red S staining and Safranin O/fast green staining of femur were employed to evaluate bone microstructure, bone metabolism and bone development.The expressions of cathepsin K were assessed by Western blot and immunohistochemical staining.Results Histopathological results showed that curcumin could improve the destruction of trabecular bone structure, cartilage development and bone calcification.Biomechanical results proved that curcumin could improve the bone strength of the type 2 diabetic mice induced by high fat.The results of immunohistochemistry and Western blot assay indicated that curcumin could significantly inhibit the expression of cathepsin K in bone tissues of mice.Conclusion Curcumin can increase bone strength, improve bone microstructure, and enhance the degree of bone calcification, which may be achieved by inhibiting the expression of cathepsin K.